Structure of the Myotonic Dystrophy Type 2 RNA and Designed Small Molecules That Reduce Toxicity
详细信息 查看全文
- 作者：Jessica L. Childs-Disney ; Ilyas Yildirim ; HaJeung Park ; Jeremy R. Lohman ; Lirui Guan ; Tuan Tran ; Partha Sarkar ; George C. Schatz ; Matthew D. Disney
- 刊名：ACS Chemical Biology
- 出版年：2014
- 出版时间：February 21, 2014
- 年：2014
- 卷：9
- 期：2
- 页码：538-550
- 全文大小：716K
- ISSN：1554-8937
文摘
Myotonic dystrophy type 2 (DM2) is an incurable neuromuscular disorder caused by a r(CCUG) expansion (r(CCUG)exp) that folds into an extended hairpin with periodically repeating 2脳2 nucleotide internal loops (5鈥睠CUG/3鈥睪UCC). We designed multivalent compounds that improve DM2-associated defects using information about RNA鈥搒mall molecule interactions. We also report the first crystal structure of r(CCUG) repeats refined to 2.35 脜. Structural analysis of the three 5鈥睠CUG/3鈥睪UCC repeat internal loops (L) reveals that the CU pairs in L1 are each stabilized by one hydrogen bond and a water-mediated hydrogen bond, while CU pairs in L2 and L3 are stabilized by two hydrogen bonds. Molecular dynamics (MD) simulations reveal that the CU pairs are dynamic and stabilized by Na+ and water molecules. MD simulations of the binding of the small molecule to r(CCUG) repeats reveal that the lowest free energy binding mode occurs via the major groove, in which one C residue is unstacked and the cross-strand nucleotides are displaced. Moreover, we modeled the binding of our dimeric compound to two 5鈥睠CUG/3鈥睪UCC motifs, which shows that the scaffold on which the RNA-binding modules are displayed provides an optimal distance to span two adjacent loops.